Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
Mod Pathol. 2018 Jul;31(7):1107-1115. doi: 10.1038/s41379-018-0007-9. Epub 2018 Feb 15.
The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERT in multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERT promoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cord-stromal tumors including adult granulosa cell tumors. We performed whole-genome sequencing on ten adult granulosa cell tumors with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERT promoter have increased expression of TERT mRNA and exhibited significantly longer telomeres compared to those with wild-type TERT promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary adult granulosa cell tumors (22%), 24 of 58 recurrent adult granulosa cell tumors (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERT C228T promoter mutation in the primary tumors and those without it (p = 0.00253, log-rank test). In seven adult granulosa cell tumors, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERT C228T promoter mutations may have an important role in progression of adult granulosa cell tumors.
端粒酶逆转录酶（TERT）基因在干细胞中高度表达，在分化后被沉默。癌细胞可以通过激活 TERT 来维持端粒长度和端粒酶活性，从而获得永生，这是肿瘤发生的关键步骤。TERT 启动子中的两个体细胞突变（C228T；C250T）已被确定为功能获得性突变，可促进多种癌症（如黑色素瘤和胶质母细胞瘤）中 TERT 的转录激活。最近一项研究调查了卵巢癌中的 TERT 启动子突变，发现透明细胞癌中有 15.9%存在 C228T 和 C250T 突变。然而，目前尚不清楚这些突变在其他卵巢癌亚型中是否频繁，特别是包括成人颗粒细胞瘤的性索-间质肿瘤。我们对 10 例成人颗粒细胞瘤进行了全基因组测序，并在 50%的肿瘤中发现了 TERT C228T 启动子突变。我们发现，与野生型 TERT 启动子相比，携带突变 TERT 启动子的成人颗粒细胞瘤中 TERT mRNA 的表达增加，并且端粒明显更长。使用等位基因鉴别进行扩展队列分析显示，在 229 例原发性成人颗粒细胞瘤中，有 51 例（22%）存在 TERT C228T 突变，在 58 例复发性成人颗粒细胞瘤中，有 24 例（41%）存在 TERT C228T 突变，在 22 例其他性索-间质肿瘤中，有 1 例（5%）存在 TERT C228T 突变。在原发性肿瘤中存在 TERT C228T 启动子突变的患者与不存在该突变的患者之间的总生存率存在显著差异（p=0.00253，对数秩检验）。在 7 例成人颗粒细胞瘤中，我们发现复发性肿瘤中存在 TERT C228T 突变，而相应的原发性肿瘤中不存在该突变。我们的数据表明，TERT C228T 启动子突变可能在成人颗粒细胞瘤的进展中发挥重要作用。
